Crystals of benzimidazole compounds

ABSTRACT

Crystals of (S)-2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole or salts thereof, useful as excellent antiulcer drugs.

This application is a 371 of PCT/JP00/04279 filed Jun. 29, 2000.

TECHNICAL FIELD

The present invention relates to crystals of a benzimidazole compoundthat possesses an antiulcer action.

BACKGROUND ART

2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof, which possess an antiulcer activity, has beendescribed in JP 61-50978 A and the like.

DISCLOSURE OF THE INVENTION

2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolepossesses a chiral sulfur within the molecule, and two kinds of opticalisomers thereof exist. As a result of intensive investigations, thepresent inventors have succeeded in the optical resolution andcrystallization of the (S) isomer of2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleand have found for the first time that the crystals are satisfactoryenough for drugs, thereby having completed the present invention on thebasis of these findings.

In other words, the present invention relates to

(1) crystals of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof,

(2) crystals of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,

(3) the crystals as described in the above (2) which possess a patternof the powder X-ray diffraction whose characteristic peaks appear at thelattice spacing (d) of the powder X-ray diffraction of 11.68, 6.78,5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11 angstrom (Å),

(4) a pharmaceutical composition comprising the crystals as described inthe above (1) and the like.

As for the“salt” of“(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof”, a physiologically acceptable salt is preferred,which is exemplified by a metal salt, a salt with an organic base, asalt with a basic amino acid or the like.

Examples of a metal salt include an alkaline metal salt such as sodiumsalt, potassium salt, etc., an alkaline earth metal salt such as calciumsalt, magnesium salt, barium salt, etc., and the like. A salt with anorganic base is exemplified by a salt with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine or thelike. A salt with a basic amino acid is exemplified by a salt witharginine, lysine or the like.

Crystals of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof may be a hydrate or a non-hydrate.

Said “hydrate” is exemplified by a 0.5 to 5.0 hydrate. Among them, 0.5hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate, or 2.5 hydrate ispreferable. Particularly preferred is 1.5 hydrate.

Crystals of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof can be obtained by subjecting2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof to optical resolution or by subjecting2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazoleor a salt thereof to asymmetric oxidation to obtain the (S)-isomer,followed by crystallization.

Examples of a method used for the optical resolution include a per seknown method such as a fractional recrystallization method, a chiralcolumn method, a diastereomer method and the like. As asymmetricoxidation, a per se known method is used.

The “fractional recrystallization method” is exemplified by a method, inwhich the racemate is treated with an optically active compound [e.g.,(+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaricacid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine,(−)-cinchonidine, brucine, etc.) to form the salts, followed byseparation by a fractional recrystallization or the like, and,optionally, by subjecting the resultant to a neutralization step toobtain the optical isomer in the free form.

The “chiral column method” is exemplified by a method, in which theracemate or a salt thereof is applied to a column for separation ofoptical isomers (a chiral column). In the case of liquid chromatography,for instance, there is exemplified a method, in which the racemate isadded to a chiral column such as ENANTIO-OVM (manufactured by TosoCorporation), CHIRAL series manufactured by Daicel Company or the like,which is eluted with water, a buffer solution (e.g., a phosphate buffersolution), an organic solvent (e.g., hexane, ethanol, methanol,isopropanol, acetonitrile, trifluoroacetic acid, diethylamine,triethylamine, etc.) or a mixed solvent thereof to separate the opticalisomers. In the case of gas chromatography, for instance, a separationmethod using a chiral column such as CP-Chirasil-DeX CB (manufactured byG-L Sciences Inc.) or the like is exemplified.

The “diastereomer method” is exemplified by a method, in which theracemate is allowed to react with an optically active reagent(preferably, to react with the optically active reagent at position 1 ofthe benzimidazole group) to obtain a mixture of the diastereomers,followed by treatment with a conventional separation means (e.g.,fractional recrystallization, chromatography method, etc.) to obtain oneof the diastereomers, which is then subjected to a chemical reaction(e.g., acid hydrolysis reaction, basic hydrolysis reaction,hydrogenolysis reaction, etc.) to cleave the moiety of the opticallyactive reagent, thereby obtaining the objective optical isomer. Examplesof said “optically active reagent” include optically active organicacids such as MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid],(−)-menthoxyacetic acid and the like; optically active alkoxymethylhalides such as(1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane, andthe like.

2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof is produced according to the method described in JP61-50978 A, U.S. Pat. No. 4,628,098 or the like, or a modified methodthereof.

Examples of the method for crystallization include a per se known methodsuch as crystallization from a solution, crystallization from a vapor,and crystallization from a melt.

Examples of the method for said “crystallization from a solution”include a concentration method, a slow cooling method, a reaction method(diffusion method or electrolysis method), a hydrothermal formationmethod, a fluxing agent method and the like. Examples of the solvent tobe used include aromatic hydrocarbons (e.g., benzene, toluene, xylene,etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane,etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, etc.), nitrites (e.g., acetonitrile, etc.), ketones (e.g.,acetone, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), acid amides(e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.),alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), water andthe like. These solvents are used alone or in combination of two or morethereof in an adequate ratio (for example, 1:1 to 1:100).

Examples of the method for said “crystallization from a vapor” includean evaporation method (a sealed tube method or an air stream method), avapor phase reaction method, a chemical transportation method or thelike.

Examples of the method for said “crystallization from a melt” include anormal freezing method (pulling-up method, temperature gradient methodor Bridgman method), a zone melting method (zone leveling method orfloat zone method), a special growth method (VLS method or liquid-phaseepitaxy method) and the like.

As for an method for analyzing the thus-obtained crystals, generally,crystal analysis by a X-ray diffraction method is employed. Furthermore,a method for determining the orientation of crystals is exemplified by amechanical method, an optical method or the like.

The thus-obtained crystals of(S)-2-[[[3-methyl-4-(2,2,3-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof (hereinafter, sometimes, abbreviated as “the crystalsof the present invention”) possesses an excellent antiulcer activity, ananti-gastric acid secreting activity, a mucous membrane protectingactivity, an anti-Helicobacter pylori activity and the like, and isuseful as drugs owing to the low toxicity. Moreover, crystallization ofthe S-form not only increases the stability but also facilitates thehandling of the compound, thereby making it possible to manufacturesolid pharmaceutical compositions in a reproducible manner. Also, ashorter duration of the pharmacological activity is obtained in the caseof administration of the crystals of the present invention, resulting inallowing a long-term administration.

The crystals of the present invention are useful for therapeutics andprophylaxis of a peptic ulcer (e.g., gastric ulcer, duodenal ulcer,stomal ulcer, Zollinger-Ellison's syndrome, etc.), gastritis, refluxesophagitis, NUD (non-ulcer dyspepsia), stomach cancer, gastric MALTlymphoma and the like, eradication of Helicobacter pylori, suppressionof bleeding of upper gastrointestinal tract caused by peptic ulcer,acute stress ulcer and hemorrhagic gastritis, suppression of bleeding ofupper gastrointestinal tract caused by invasive stress (stress caused bymajor surgery requiring postoperative intensive care, cerebrovasculardisorder requiring intensive treatment, head injury, multiple organfailure and extensive burn), therapeutics and prophylaxis of ulcercaused by a nonsteroidal antiinflammatory agent; therapeutics andprophylaxis of hyperacidity and ulcer caused by postoperative stress;pre-anesthetic medication, and the like, in mammals (e.g., human,monkey, sheep, cow, horse, dog, cat, rabbit, rat, mouse, etc.).

The crystals of the present invention are low in the toxicity and can besafely administered orally or parenterally (for example, local, rectaland intravenous administrations, or the like) as they are or as any ofpharmaceutical compositions, which are prepared by mixing withpharmacologically acceptable carriers according to a per se knownmethod, such as, for example, tablets (including sugar-coated tabletsand film-coated tablets), powders, granular preparations, capsules(including soft capsules), oral disintegrating tablets, solutions,injectable preparations, suppositories, sustained release preparations,patches and the like.

The content of the crystals of the present invention in thepharmaceutical compositions of the present invention is about 0.01 to100% by weight based on the total weight of the composition. Althoughthe dose of any of said pharmaceutical compositions varies depending onparticular patient, route of administration, disease and the like, inthe case of oral administration to an adult (60 kg) as an antiulceragent, for instance, the dose is about 0.5 to 1500 mg/day as the activeingredient, preferably about 5 to 150 mg/day. The daily dosage of thecrystals of the present invention may be administered at once or dividedinto 2 to 3 times per day.

As for the pharmacologically acceptable carriers that may be used forthe manufacture of the pharmaceutical compositions of the presentinvention, there are used a variety of conventional pharmaceuticallyacceptable organic or inorganic carrier substances, for example,excipients, lubricants, binding agents, disintegrators, water-solublehigh molecular substances and basic inorganic salts for solidpreparations; solvents, solubilizing agents, suspending agents,isotonicity agents, buffering agents and analgesics for liquidpreparations, and the like. Also, as needed, additives such asconventional preservatives, antioxidants, coloring agents, sweeteners,acidifiers, foaming agents, flavors and the like can be used.

Examples of said “excipients” include lactose, white soft sugar,D-mannitol, starch, corn starch, crystalline cellulose, light anhydroussilicic acid, titanium oxide and the like.

Examples of said “lubricants” include magnesium stearate, a sucrosefatty acid ester, polyethylene glycol, talc, stearic acid and the like.

Examples of said “binding agents” include hydroxypropyl cellulose,hydroxypropylmethyl cellulose, crystalline cellulose, α-starch,polyvinyl pyrrolidone, gum arabic, gelatin, Pullulan, low-substitutedhydroxypropyl cellulose and the like.

Examples of said “disintegrators” include (1) crospovidon, (2) adisintegrator that is designated as a super disintegrator such ascroscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (GotokuYakuhin) or the like, (3) carboxymethyl starch sodium (e.g.,manufactured by Matsutani Kagaku Kabushiki Kaisha), (4) alow-substituted hydroxypropyl cellulose (e.g., manufactured by Shin-EtsuKagaku Kabushiki Kaisha), (5) corn starch, and the like. Said“crospovidon” may be any of crosslinked polymers that have a chemicalname of 1-ethenyl-2-pyrrolidinone homopolymer, including polyvinylpolypyrrolidone (PVPP) and so-called 1-vinyl-2-pyrrolidinonehomopolymer, where specific examples include Kollidon CL (manufacturedby BASF AG), Polyplasdon XL (manufactured by ISP Company), PolyplasdonXL-10 (manufactured by ISP Company), Polyplasdon INF-10 (manufactured byISP Company) and the like.

Examples of said “water-soluble high molecular substances” include anethanol-soluble, water-soluble high molecular substance [for example, acellulose derivative such as hydroxypropyl cellulose (hereinafter, maybe described as HPC), polyvinyl pyrrolidone and the like], anethanol-insoluble, water-soluble high molecular substance [for example,a cellulose derivative such as hydroxypropylmethyl cellulose(hereinafter, may be described as HPMC), methyl cellulose orcarboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol,sodium alginate, guar gum and the like] and the like.

Examples of said “basic inorganic salts” include a basic inorganic saltof sodium, potassium, magnesium and/or calcium. Preferably, it is abasic inorganic salt of magnesium and/or calcium. More preferably, it isa basic inorganic salt of magnesium. Examples of said basic inorganicsalt of sodium include sodium carbonate, sodium hydrogen carbonate,disodium hydrogen phosphate and the like. Examples of said basicinorganic salt of potassium include potassium carbonate, potassiumhydrogen carbonate and the like. Examples of said basic inorganic saltof magnesium include magnesium carbonate heavy, magnesium carbonate,magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate,magnesium silicate, magnesium aluminate, synthetic hydrotalcite[Mg₆Al₂(OH)₁₆·CO₃·4 H₂O] and alumina magnesium hydroxide, preferablymagnesium carbonate heavy, magnesium carbonate, magnesium oxide,magnesium hydroxide and the like. Examples of said basic inorganic saltof calcium include precipitated calcium carbonate, calcium hydroxide andthe like.

Examples of said “solvents” include water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil and thelike.

Examples of said “solubilizing agents” include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisamiomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate and thelike.

Examples of said “suspending agents” include, a surface active agentsuch as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate or the like; a hydrophilic, highmolecular substance such as, for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl celluloseor the like, and the like.

Examples of said “isotonicity agents” include glucose, D-sorbitol,sodium chloride, glycerin, D-mannitol and the like.

Examples of said “buffering agents” include a buffer solution of aphosphate, an acetate, a carbonate, a citrate or the like, and the like.

Examples of said “analgesics” include benzyl alcohol and the like.

Examples of said “preservatives” include a paraoxybenzoic acid ester,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of said “antioxidants” include a sulfite salt, ascorbic acid,α-tocopherol and the like.

Examples of said “coloring agents” include a food dye such as foodyellow No. 5, food red No. 2, food blue No. 2 or the like; edible lakedye, iron oxide red and the like.

Examples of said “sweeteners” include saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia, somatin and the like.

Examples of said “acidifiers” include citric acid (anhydrous citricacid), tartaric acid, malic acid and the like.

Examples of said “foaming agents” include sodium bicarbonate and thelike.

Examples of said “flavors”, which may be either synthetic or naturallyoccurring, include lemon, lime, orange, menthol, strawberry and thelike.

The oral preparations can be manufactured according to a per se knownmethod by adding to the crystals of the present invention, for examples,a bulking agent, a disintegrator, a binding agent, a lubricant and thelike, and by subjecting the resulting mixture to compression molding, asneeded, followed by coating according to a per se known method for thepurpose of masking of the taste, enteric coating or durability. In thecase of the manufacture of an enteric coated preparation, anintermediary phase may be provided between the enteric coated phase andthe drug-containing phase, according to a per se known method, for thepurpose of separating both phases.

In the case where the crystals of the present invention are used for themanufacture of an oral rapidly disintegrating tablet, there isexemplified a method comprising coating a core containing crystallinecellulose and lactose with the crystals of the present invention and abasic inorganic salt, followed by further coating with a coating layercontaining a water-soluble high molecular substance to obtain acomposition, coating the thus-obtained composition with an entericcoating layer containing polyethylene glycol, coating with an entericcoating layer containing triethyl citrate, coating with an entericcoating layer containing polyethylene glycol, further coating withmannitol to obtain fine granules, mixing the thus-obtained fine granuleswith an excipient and molding, or the like. Examples of theabove-described “enteric coating layer” include one or more of anaqueous-type enteric high molecular base such as cellulose acetatephthalate (CAP), hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate succinate, a methacrylate copolymer [e.g., EudragitL30D-55 (trade name; manufactured by Rohm Company), Kollicoat MAE30DP(trade name; manufactured by BASF AG), Poliquid PA30 (trade name;manufactured by Sanyo Kasei Company), etc.], carboxymethylethylcellulose, shellac or the like; a sustained-release base such as amethacrylate copolymer [e.g., Eudragit NE30D (trade name), EudragitRL30D (trade name), Eudragit RS30D (trade name), etc.] or the like; awater-soluble high molecular substance; plasticizers such as triethylcitrate, polyethylene glycol, acetylated monoglyceride, triacetin,castor oil, etc., and the like. Examples of the above-described“additives” include a water-soluble sugar alcohol (e.g., sorbitol,mannitol, maltitol, reducing saccharized starch, xylitol, reducingpalatinose, erythritol, etc.), crystalline cellulose (e.g., Ceolus KG801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, AvicelRC-591 (crystalline cellulose/carmellose sodium), etc.), a lowsubstitution degree hydroxypropyl cellulose (e.g., LH-22, LH-32, LH-23,LH-33 (Shin-Etsu Kagaku Kabushiki Kaisha), a mixture thereof, etc.) orthe like, where there are further used a binding agent, an acidifier, afoaming agent, a sweetener, a flavor, a lubricant, a coloring agent, astabilizer, an excipient, a disintegrator and the like.

The crystals of the present invention may be used together with 1 to 3kinds of other active components.

Examples of said “other active components” include an anti-Helicobacterpylori substance, an imidazole compound, a bismuth salt, a quinolonecompound and the like. Among these, an anti-Helicobacter pylorisubstance, an imidazole compound and the like are preferable. Examplesof said “anti-Helicobacter pylori substance” include a penicillinantibiotic (e.g., amoxicillin, benzyl penicillin, piperacillin,mecillinam, etc.), a cephem antibiotic (e.g., cefixime, cefaclor, etc.),a macrolide antibiotic (e.g., erythromycin, clarithromycin, etc.), atetracycline antibiotic (e.g., tetracycline, minocycline, streptomycin,etc.), an aminoglycoside antibiotic (e.g., gentamycin, amikacin, etc.),imipenem and the like. A penicillin antibiotic, a macrolide antibioticand the like are especially preferable. Examples of said “imidazolecompound” include metronidazole, miconazole and the like. Examples ofsaid “bismuth salt” include bismuth acetate, bismuth citrate and thelike. Examples of said “quinolone compound” include ofloxacin,ciproxacin and the like.

Said “other active components” and the crystals of the present inventionmay be mixed and formulated into a single pharmaceutical composition(e.g., a tablet, a powder, a granule preparation, a capsule (including asoft capsule), a liquid and solution, an injection, a suppository, asustained release preparation, etc.) according to a per se known method,or may be formulated separately and administered to the same subject atthe same time or at a certain interval.

The following Reference Examples and Examples further illustrate thepresent invention in more detail, but they are not intended to limit thepresent invention.

In the following Reference Examples and Examples, room temperature meansa temperature of about 15 to 30° C.

The melting points were measured by the use of a Micro Melting PointApparatus (manufactured by Yanagimoto Seisakusho), and uncorrectedvalues are shown.

The ¹H-NMR spectra were measured by the use of a Varian Gemini-2000using CDCl₃ as a solvent, and the chemical shifts δ (ppm) fromtetramethylsilane used as the internal standard are shown.

The IR spectra were measured with a SHIMAZU FTIR-8200.

The UV spectra were measured with a HITACHI U-3200 Spectrophotometer.

The optical rotations [α_(D)] were measured at 20° C. by the use of aDIP-370 Digital polarimeter (manufactured by Nihon Bunko (JASCO)).

The measurement of optical purity was conducted by HPLC using a chiralcolumn (column: CHIRALCEL OD 4.6 mm φ×250 mm, temperature: about 20° C.,mobile phase: hexane/2-propanol=80/20 or hexane/2-propanol=85/15, flowrate: 1.0 mL/minute, detection wavelength: 285 nm).

The crystal data of X-ray diffraction analysis for determining theabsolute structure of the sulfoxide were measured by the use of a4-circle diffractometer (RIGAKU AFC5R) using the Cu-Kα radiation. Aninitial phase was determined by the direct method, and the structure wasrefined with a SHELXL-93. The powder X-ray diffraction was measured bythe use of an X-ray Powder Diffractometer Rigaku RINT 2500 (ultra X18)No. PX-3.

The other symbols in the present specification indicate the followingmeanings.

S: singlet

d: doublet

t: triplet

q: qualtet

m: multiplet

bs: broad singlet

J: coupling constant

REFERENCE EXAMPLE 1 Preparative Separation of(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-Lansoprazole)

2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(lansoprazole) (racemate) (3.98 g) dissolved in the mobile phasedescribed below (330 mL) and acetonitrile (37 mL) was fractionated byHPLC (column: CHIRALCEL OD 20 mm φ×250 mm, temperature: 30° C., mobilephase: hexane/2-propanol/ethanol=255/35/10, flow rate: 16 mL/minute,detection wavelength: 285 nm, one shot: 20 to 25 mg). The fractions ofthe optical isomer having a longer retention time were collected andwere concentrated, all lots were combined and were dissolved in ethanol,the resulting solution was filtered through a 0.45 μm filter and thefiltrate that was mixed with hexane was evaporated to dryness again toobtain S(−)-lansoprazole (1.58 g, an optical purity of 92.6% ee) as anamorphous material.

The thus-obtained amorphous material was fractionated again in the sameway as described above to obtain S(−)-lansoprazole (0.94 g, an opticalpurity of 99.0% ee) as an amorphous substance.

[α_(D)]=−175.4° (c=1.003%, CHCl₃)

REFERENCE EXAMPLE 2 Preparative Separation of(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-Lansoprazole)

Lansoprazole (racemate) (34.2 g) dissolved in 2-propanol (1710 mL) andhexane (1140 mL) containing triethylamine (0.2%) was fractionated byHPLC (column: CHIRALCEL OD 50 mm φ×500 mm, temperature: roomtemperature, mobile phase: hexane/2-propanol =85/15, flow rate: 60mL/minute, detection wavelength: 285 nm, one shot: about 300 mg). Thefractions of the optical isomer having a longer retention time werecollected and were concentrated, all lots were.combined and weredissolved in ethanol (250 mL) and the resulting solution, into whichtriethylamine (3 mL) was added, was then filtered through a 0.45 μmfilter. The filtrate was concentrated, was mixed with hexane and wasevaporated again to dryness to obtain S(−)-lansoprazole (9.15 g, anoptical purity of 93.3% ee) as an amorphous substance.

REFERENCE EXAMPLE 3 Preparative Separation of(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-Lansoprazole)

Lansoprazole (racemate) (4.1 g) dissolved in the mobile phase describedbelow (100 mL) and ethanol (100 mL) was fractionated by HPLC (column:CHIRALCEL OD 50 mm φ×500 mm, temperature: 30° C., mobile phase:hexane/2-propanol=85/15, flow rate: 60 mL/minute, detection wavelength:285 nm, one shot: 260 to 300 mg). The fractions of the optical isomerhaving a longer retention time were collected and were concentrated, alllots were combined and were dissolved in ethanol, the resulting solutionwas filtered through a 0.45 μm filter and the filtrate that was mixedwith hexane was evaporated to dryness again to obtain S(−)-lansoprazole(1.6 g) as an amorphous material.

The thus-obtained amorphous material was fractionated again in the sameway as described above to obtain S(−)-lansoprazole (1.43 g, an opticalpurity of 97.4% ee) as an amorphous substance.

EXAMPLE 1 Crystals of(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-Lansoprazole)

The amorphous S(−)-lansoprazole (400 mg) obtained in Reference Example 3was dissolved in ethanol (20 mL), and the resulting solution wasdecolorized by treatment with an activated charcoal to obtain a yellowamorphous material (320 mg). The thus-obtained amorphous material (40mg) was dissolved in isopropanol (0.3 mL) and was mixed with n-hexane (1mL). The mixture was kept in a refrigerator for one week, and thethus-obtained single crystals were subjected to the X-ray structureanalysis to reveal that the absolute configuration of the sulfoxide isthe S configuration according to a judgment method by the use of theFlack parameters.

TABLE 1 Crystal data and parameters for structure refinement Molecularformula: C₁₆H₁₄N₃O₂F₃S Molecular weight: 369.36 Color and shape of thecrystal: colorless, plate Size: 0.40 × 0.20 × 0.20 (mm) Crystal system:monoclinic Cell parameters: a = 8.545 (1) (Å) b = 23.3495 (2) (Å) c =8.723 (1) (A) β = 103.88 (1) (°) V = 1689.8 (4) (Å³) Space group: P2₁ Z:4 Density (calculated): 1.452 (g/cm³) The number of effectivereflections/the 11.22 number of parameters: R (I ≧ 2σ (I)): 0.037 Flackparameters: 0.02 (2)

EXAMPLE 2 Crystals of(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-Lansoprazole)

To the amorphous(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(9.04 g) obtained in Reference Example 2, which was dissolved in acetone(25 mL), was added water (15 mL) with slight heating. The resultingmixture was allowed to stand at room temperature overnight, was thenmixed with water (10 mL) and was sonicated. The solid material wascollected by filtration, washed with water (35 mL, 25 mL) and thenwashed with diisopropyl ether (10 mL). The resulting material was driedunder reduced pressure to obtain a solid material (8.51 g). A solutionof the thus-obtained solid material (8.41 g) in acetone (30 mL) wasfiltered, and diisopropyl ether (50 mL) was then added to the filtrate.Small crystals were added therein and the resulting mixture was allowedto stand at room temperature overnight. The precipitated crystals werecollected by filtration and were washed three times with diisopropylether (10 mL). The resulting crystals were dried under reduced pressureto obtain crystals (6.39 g). The thus-obtained crystals (6.39 g) weredissolved in acetone (35 mL) and water (30 mL) with heating, and theresulting solution was allowed to stand at room temperature for 1 hour.The precipitated crystals were collected by filtration, were washed withacetone-water (1:4) (15 mL) and were dried under reduced pressure toobtain crystals (3.54 g). The thus-obtained crystals (3.54 g) weredissolved in acetone (4 mL) with heating and thereto was addeddiisopropyl ether (14 mL). The resulting mixture was allowed to stand atroom temperature for 30 minutes and was then sonicated. The precipitatedcrystals were collected by filtration, were washed twice withdiisopropyl ether and were dried under reduced pressure to obtain thecrystals of S(−)-lansoprazole (3.33 g, optical purity 99.4% ee).

mp: 146.0-147.0° C. (decomposed).

Elemental analysis

Calcd.: C, 52.03; H, 3.82; N, 11.38; S, 8.68; F, 15.43; O, 8.66.

Found: C, 51.96; H, 4.06; N, 11.20; S, 8.88; F, 15.40.

¹H-NMR: 2.24 (3H, s), 4.39 (2H, q, J=7.8 Hz), 4.72 (1H, d, J=13.9 Hz),4.87 (1H, d, J=13.9 Hz), 6.68 (1H, d, J=5.8 Hz), 7.27-7.37 (2H, m), 7.48(1H, m), 7.79 (1H, m), 8.36 (1H, d, J=5.8 Hz).

IR (v cm⁻¹): 3083, 3036, 2967, 1584, 1478, 1441, 1306, 1267, 1163.

UV_(max) (CHCl₃): 283.9 nm. [α]_(D)=−179.1° (c=0.995%, CHCl₃).

TABLE 2 Data of powder X-ray diffraction Half-valence Relative 2θ (°)breadth d Value (Å) intensity (%) 7.560 0.141 11.6841 92 13.040 0.1416.7836 65 15.140 0.165 5.8471 49 15.440 0.141 5.7342 100 20.020 0.1654.4315 32 21.700 0.141 4.0920 99 22.540 0.141 3.9414 30 22.780 0.1653.9004 24 24.080 0.141 3.6927 46 26.120 0.188 3.4088 39 28.680 0.2823.1100 28

EXAMPLE 3 Crystals of(S)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-Lansoprazole) 1.5 Hydrate

To the amorphous(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(100 mg) obtained in Reference Example 2, which was dissolved in acetone(2 mL), was added water (2 mL). An insoluble material was removed byfiltration and acetone was then allowed to be gradually evaporated fromthe filtrate. Small crystals were added therein and the resultingmixture was allowed to stand at room temperature overnight. Theprecipitated crystals were collected by filtration, were washed twicewith diisopropyl ether (1 mL) and were dried under reduced pressure toobtain the crystals of(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(S(−)-lansoprazole) 1.5 hydrate (62 mg).

mp: 80.0-84.0° C.;

Elemental analysis;

Calcd.: C, 48.48; H, 4.32; N, 10.60; S, 8.09; F, 14.38; O, 14.13.

Found: C, 48.48; H, 4.28; N, 10.67.

TABLE 3 Data of powder X-ray diffraction Half-valence Relative 2θ (°)breadth d Value (Å) intensity (%) 6.680 0.141 13.2212 16 9.200 0.1419.6046 30 9.960 0.165 8.8734 59 10.980 0.165 8.0513 49 13.380 0.1656.6120 36 14.960 0.141 5.9170 42 15.680 0.165 5.6469 100 17.660 0.2125.0180 73 19.720 0.212 4.4982 42 24.900 0.141 3.5729 26 29.780 0.2352.9976 17

Industrial Applicability

The crystals of the present invention possess an excellent antiulceraction, an anti-gastric acid secreting action, a mucous membraneprotecting action, an anti-Helicobacter pylori action and the like, andis useful as drugs owing to the low toxicity. Moreover, crystallizationof the S-form not only increases the stability but also facilitates thehandling of the compound, thereby making it possible to manufacture thesolid pharmaceutical compositions in a reproducible manner. Also, ashorter duration of the effect is obtained in the case of theadministration of the crystals of the present invention, resulting inallowing a long-term administration.

What is claimed is:
 1. Crystals of(s)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolewhich possess a powder X-ray diffraction pattern whose characteristicpeaks appear as the lattice spacing (d) of the powder X-ray diffractionat 11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41, 3.11angstrom.
 2. A pharmaceutical composition comprising the crystals ofclaim 1 together with a pharmaceutically acceptable carrier.
 3. Crystalsof(S)-2-[[[3-methy]4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole1.5 hydrate which possess a powder X-ray diffraction pattern whosecharacteristic peaks appear as the lattice spacing (d) of the powderX-ray diffraction at 13.22, 9.60, 8.87, 8.05, 6.61, 5.92, 5.65, 5.02,4.50, 3.57, 3.00 angstrom.
 4. A pharmaceutical composition comprisingthe crystals of claim 3 together with a pharmaceutically acceptablecarrier.